The listing or discussion of an apparently prior-published document in this specification should not necessarily be taken as an acknowledgement that the document is part of the state of the art or is common general knowledge.
Metabolites of endogenous steroid hormones, such as the pregnanolones (including pregnenolone, progesterone, deoxycorticosterone, cortisone and cortisol), testosterone, androstenedione and dehydroepiandrosterone, have been the subject of various studies.
Many examples of 3-alpha-hydroxy-5-alpha/beta-steroids are known to act on the gamma-aminobutyric acid receptor-chloride ionophore (GABAA-R) complex and are therefore referred to as GABAA receptor modulating steroids (GAMS). Mechanisms of interaction at the receptor site have not yet been fully elucidated, due to the structural complexity of the GABAA-R complex. However, the GABA receptor family includes several subunit components, some of which are known to be related to specific functions and disorders of the CNS.
3-alpha-hydroxy-5-alpha/beta-steroids are produced in high amounts over several days/week, and can directly cause inhibition of CNS functions. Examples of disorders and symptoms caused by the direct action of 3-alpha-hydroxy-5-alpha/beta-steroids include premenstrual dysphoric disorder, premenstrual syndrome, dementia, Alzheimer's disease, Down's syndrome, sedation, tiredness, chronic fatigue syndrome, memory disturbance, learning disturbance, disturbance of motor function, fractures, clumsiness, increased appetite and food cravings, obesity, relapse in alcohol or substance abuse, negative mood as tension, irritability, depression, decreased hearing and eye sight, worsening of Petit Mal epilepsy and burn out syndrome.
Continuous and/or long-term exposure to 3-alpha-hydroxy-5-alpha/beta-steroids causes tolerance to develop in the GABAA receptor system. This tolerance is the first step in a process that may ultimately lead to stress sensitivity, concentration difficulties, and loss of impulse control and depression. Further, the action of 3-alpha-hydroxy-5-alpha/beta-steroids has been found to be a factor that reinforces drug dependency.
Continuous but shorter-term exposure on the other hand results in a withdrawal effect when exposure is terminated. This phenomenon occurs e.g. during menstruation, when the production of 3-alpha-hydroxy-5-alpha/beta-steroids by the corpus luteum of the ovary is interrupted. This withdrawal phenomenon also occurs after giving birth when their production by the placenta is interrupted, or at the end of a period of stress (adrenal glands produce 3-alpha-hydroxy-5-alpha/beta-steroids during stress).
Examples of conditions that are influenced by this such withdrawal and/or abstinence include partial epilepsy, “catamenial epilepsy”, migraine, mood changes and “weekend” headache.
The GABAA receptor is a chloride channel and exerts its action by changing the influx of chloride through the channel. It is known in the art that the neuronal activity in the brain is decreased when the GABAA receptor is open and large amounts of chloride ion flux into the cell. It is also known that there is a relationship between the amount of chloride moving in, and the clinical effect of a GABAA receptor active drug.
Benzodiazepines, barbiturates and, to an extent, alcohol exerts their action via this mechanism. This, however, also accounts for the adverse effects of these drugs.
A problem with the GABAA receptor is that it exerts its action in most parts of the brain. In view of this, complete blockers of GABA action are dangerous and may cause psychotic symptoms and convulsions. That said, when the action of 3-alpha hydroxy-5-alpha/beta-pregnan-steroids is to be antagonized it would be desirable to use compounds that specifically antagonize 3-alpha-hydroxy-5-alpha/beta-pregnan-steroid effects, whilst not antagonizing GABA's own effect.
Accordingly, the present invention endeavours to solve the problem of provision of specific agents that are capable of blocking GABA receptors, which compounds may thus be useful in the treatment of anomalies in the excitation of GABA receptors or other neurotransmitters related to GABA receptors.
International patent application WO 2008/063128 disclose 3-alpha-hydroxy steroids and 3-beta-hydroxy steroids. International patent application WO 99/45931 discloses antagonistic effects of the steroid 3-beta-OH-5alpha-pregnan-20-one. International patent application WO 03/059357 discloses 3-beta-hydroxy steroids and their antagonistic effect on the GABAA receptor.
U.S. Pat. Nos. 5,232,917, 5,925,630, 5,939,545, 6,143,736 and 6,277,838 disclose 3-alpha-hydroxy steroids and 3-beta-hydroxy steroids as agonistic modulators of the GABAA receptor with a specific focus on 3-alpha-hydroxy steroids and their benzodiazepine like effect. In US patent application US 2004/0242549, a number of steroids are disclosed.
The antagonistic effect of 3-beta-OH-5-alpha-pregnan-20-one and other 3-beta-OH—5-alpha/beta pregnan-steroids is discussed by Wang et al (Acta Physiol. Scand., 169, 334 (2000) and J. Neurosci., 22, 3366 (2002)).
Prior art compounds including those mentioned above are not specific to certain GABAA-R subtypes. Accordingly, there is a need for compounds that are more selective to receptor sub-types.
Additionally prior art and naturally occurring steroids are subject to metabolism, are often not suitable for oral administration, and typically have poor permeability.
This makes it very difficult to administer such compounds. Accordingly, there is also a need for compounds that are less easily metabolized/degraded in the body, and/or have an improved permeability/bioavailability.